Lymphomas represent a significant cause of morbidity and mortality in the United States with an incidence of approximately 16/100,000 population. These statistics are further compounded by the 4% annualized rise in the incidence of lymphomas with an overall 150% increase between the 1940 and 1980. Our research focus is on the development of therapeutic strategies and the study of the pathobiology of lymphoid malignancies. A principal research area is the study of aggressive B-cell lymphomas. As most of these lymphomas are potentially curable, our studies have included both novel use of approved agents as well as the study of experimental (targeted) agents. We have worked on development of the DA-EPOCH-R platform from its inception to its current use as standard treatment for aggressive B-cell lymphomas. In collaboration with Louis Staudt and extramural collaborators, we have worked on the clinical development of targeted agents for diffuse large B-cell lymphoma (DLBCL). Our efforts have primarily centered on DLBCL and its molecular subtypes activated B-cell (ABC), germinal center B cell (GCB) and primary mediastinal B-cell lymphoma (PMBL), Burkitt lymphoma (BL) and mantle cell lymphoma (MCL). As part of this effort, we have incorporated translational endpoints to better understand tumor biology, therapeutic targets, and detection of tumor using circulating tumor DNA. We have also leveraged expertise at the NIH in immunodeficiency through our study of lymphomas in immunocompromised hosts. Following is an overview of each area of study. An area of interest is mediastinal B-cell Lymphomas (PMBL and Gray Zone). These tumors are comprised of primary mediastinal B-cell lymphoma (PMBL) and mediastinal gray-zone lymphomas (MGZL). MGZL was first described at the NCI and is pathologically intermediate between PMBL and nodular sclerosis Hodgkin lymphoma. These three tumor types are hypothesized to derive from a thymic B-cell. The treatment of PMBL is suboptimal and most patients receive mediastinal radiotherapy, which a high rate of secondary cancer and heart disease, due to the inadequacy of R-CHOP treatment. We hypothesized these tumors are uniquely sensitive among DLBCL to dose-intensity and showed a 90% cure rate with DA-EPOCH-R without RT. We have also shown that MGZL is less responsive to treatment. Our molecular analyses show that most MGZL are more closely related to cHL than to PMBL. We have recently completed study of MYC rearranged B cell Lymphomas (Burkitt and MYC-R DLBCL). There have been no major advances in the treatment of BL over the past 20 years. In adults, BL regimens are toxic and have reported cures rates of 50-60%. We hypothesized that extended drug exposure was therapeutically more important than peak drug exposure. Based on these principles we studied DA-EPOCH-R in untreated BL showed a 90% cure rate and the importance of drug exposure time. We have recently completed a multi-center validation study of risk-adaptive DA-EPOCH-R in untreated BL. Preliminary results are consistent with our initial report of DA-EPOCH-R in BL. We have an active program for the development of targeted agents in lymphoma. We have a phase I/II program for the study of novel agents, including BTK, PI3K, mTOR, IMID's, JAK, and BET inhibitors; BH3 and SMAC mimetics, and immune based therapy with antibodies to CD20 and CD47. Our focus is on molecularly targeted treatment based on the molecular targets within tumor types and on rational combinations. These studies range from phase Ib to phase II and include single agents, doublets and multiple combinations administered in novel schedules. All our studies rise from programmatic areas of importance to our Branch and include multiple translational endpoints. While most of these studies are investigator-initiated, we also collaborate with companies to conduct novel studies for which we are the lead clinical and translational center.